WO1990004396A1 - Antiemesis ergoline derivatives - Google Patents
Antiemesis ergoline derivatives Download PDFInfo
- Publication number
- WO1990004396A1 WO1990004396A1 PCT/EP1989/001263 EP8901263W WO9004396A1 WO 1990004396 A1 WO1990004396 A1 WO 1990004396A1 EP 8901263 W EP8901263 W EP 8901263W WO 9004396 A1 WO9004396 A1 WO 9004396A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- formula
- hydrogen atom
- emesis
- compound
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Abstract
Compounds of formula (I), wherein n is 1 or 2, R1 represents a hydrogen atom or a C1-C4 alkyl group, R2 represents a hydrogen atom and R3 represents a hydrogen atom or a hydroxy group or R2 and R3 together represent a chemical bond, R4 represents a hydrogen atom, or a phenyl or C1-C4 alkyl group, R5 represents a C1-C4 alkyl group or an allyl group and R6 represents a hydrogen or halogen atom, and the pharmaceutically acceptable salt thereof, are useful for the manufacture of a pharmaceutical composition useful in the treatment of emesis.
Description
ANTIEMESIS ERGOLINE DERIVATIVES
The present invention relates to a new therapeutic use of ergoline derivatives having the formula I
wherein n is 1 or 2, R1 represents a hydrogen atom or a C1-C4 alkyl group, R2 represents a hydrogen atom and R3 represents a hydrogen atom or a hydroxy group or R2 and R3 together represent a chemical bond, R4 represents a hydrogen atom or a phenyl or C1-C4 alkyl group, R3 represents a C1-C4 alkyl group or an allyl group and R6 represents a hydrogen or halogen atom; and the pharmaceutically acceptable salts thereof.
The compounds of the formula I and their preparation are described in EP-A-0197241 or can be prepared by
techniques analogous to those described in EP-A-0197241. EP-A-0197241 shows the functional anti-dopaminergic activity of certain ergoline derivatives in normal mice. The
compounds are said to have moderate to good
anti-hypertensive activity and to be useful as anxiolytic and antipsychotic agents.
It has been found that the ergoline derivatives of the formula I may be unexpectedly used in the treatment of other diseases different from psychosis and anxiety. The compounds of formula (I) block the emetic response induced by cytotoxic agents such as cisplatin and also by radiation treatment. The compounds are therefore of use in the treatment of nausea and vomiting associated with cancer therapy.
Accordingly, the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a
pharmaceutical composition for treating emesis. The
pharmaceutical composition containing the compound of formula I or salt thereof as active agent can therefore be prepared by a process characterised in that the active agent, which has been prepared in a known way, is admixed with a pharmaceutically acceptable carrier and/or diluent and then transformed into a pharmaceutical preparation suitable for treating emesis.
The invention further provides:
- an agent for use in treating emesis, comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and
- a method of treating emesis, which method comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
In formula (I), a C1-C4 alkyl group may be a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or t-butyl group. R1 is generally a hydrogen atom or a methyl or iso-propyl group, preferably a hydrogen atom or a methyl group.
R4 is preferably methyl or hydrogen. R5 may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, iso-butyl or allyl. Preferably R5 is methyl. When R6 is halogen, it may be fluorine, chlorine or bromine.
Preferably R6 is chlorine or bromine or hydrogen.
The wavy lines
in formula I indicate that the substituents in the 8- or 9-position may be either in the α-configuration, i.e. below the plane of the ring, or in the β-configuration, i.e. above the plane of the ring, or in both, i.e. a mixture thereof such as a diasteroisomer.
Preferably the substituent in the 8-position is in the β-configuration and the substituent in 9-position is in the
α-configuration.
Preferred ergoline derivatives for use in the present invention are identified in Table I.
6-Methyl-9,10-didehydro-8α-(3,5-dioxopiperazin-l-yl-methyl)- ergoline ( I :R1 =R4 =R6 =H, R5 =CH3, R2+R3=bond, n=1) 6-Allyl-9,10-didehydro-8β-(3,5-dioxopiperazin-1-yl-methyl)- ergoline (I :R1=R4=R6=H, R5 =allyl, R2 +R3 =bond , n=1)
6-Propyl-9,10-didehydro-8α-(3,5-dioxopiperazin-1-yl-methyl) ergoline ( I:R1=R4=R6=H, R5=propyl, R2+R3=bond, n=1)
2-Chloro-6-methyl-9,10-didehydro-8β-(3,5-dioxopiperazin-1 yl-methyl)-ergoline ( I:R1=R4=H, R5=CH3 , R6=Cl, R2+R3=bond, n-1)
2-Bromo-6-methyl-9,10-didehydro-8β-(3,5-dioxopiperazin-l yl-methyl)-ergoline (I:R1=R4=H, R5 =CH3 , R6=Br, R2+R3=bond, n=1), mp. 242-245°C. 1,6-Dimethyl-9,10-didehydro-8β-(3,5-dioxo-piperazin-1-yl- methyl)-ergoline ( I :R1 =R5=CH3 , R4=R6=H, R2+R3 = bond, n=1), m.p. 216-218°C.
6-Methyl-9,10-didehydro-8β-(3,5-dioxo-piperazin-1-ethyl)- ergoline ( I:R1 =R4 =R6 =H, R5 =CH3 , R2 +R3 = bond, n=2), m.p. 242-244°C.
6-Methyl-9α-hydroxy-8β-(3,5-dioxo-piperazin-1-ylmethyl)- ergoline (I: R1=R2=R4 =R6=H, R5 =CH3 , R3=OH, n=1), m.p.
278-280°C.
6-Methyl-9,10-didehydro-8β-(3,5-dioxo-4-phenyl-piperazin-1-
ylmethyD-ergoline (I: R1=R6=H, R5=CH3, R2 +R3 = bond, R4 = phenyl, n-1) m.p. 240-242°C.
6-Methyl-9,10-didehydro-8β-(3,5-dioxo-4-methyl-piperazin- 1-ylmethyl)-ergoline (I: R1=R6=H, R4 =R5 =CH3 , R2 +R3 = bond, n=1) m.p. 227-229°C.
1-Methylethyl-6-methyl-9,10-didehydro-8β-(3,5-dioxopiperazin-1-yl-methyl)-ergoline (I: R4=R6=H, R1=i-C3H7, R5=CH3, R2+R3 = bond, n=1), m.p. 137-140°C.
6-Propy1-9,10-didehydro-8β-(3,5-dioxo-piperazin-1-yl
methyl)-ergoline (I: R1=R4=R6=H, R5=n - C3H7, R2+R3 = bond, n-1), m.p. 250-253°C.
1-Ethyl-6-methyl-9,10-didehydro-8β-(3,5-dioxo-piperazin-1- ylmethyl)-ergoline (I: R1=R4=R6=H, R5 =C2 H5 , R2 +R3 = bond, n-1) m.p. 221-223°C. The ergoline derivatives of formula I and their pharmaceutically acceptable salts are useful in the
treatment of emesis induced by cytotoxic agents. Thus, they may be used for the preparation of medicaments effective in the treament of nausea and vomiting associated with cancer therapy.
Accordingly, the compounds of formula (I) and their pharmaceutically acceptable salts can be used to treat emesis induced by cytotoxic agents by administering to a patient in need of said treatment a therapeutically
effective amount of a said compound or salt.
Examples of cytotoxic agents include those routinely used in cancer chemotherapy, such as cisplatin, doxorubicin, cyclophosphamide, particularly cisplatin. The
administration of the compound of formula (I), or a
pharmaceutically acceptable salt thereof may be by way of oral or parenteral administration.
An amount effective to treat the disorders
hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
However, a unit dose for a 70kg adult will normally contain 0.5 to 100 mg of the compound of formula (I), or a
pharmaceutically acceptable salt thereof.
Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.001 to 50mg/kg/day, more usually 0.002 to 25mg/kg/day. No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.
ADMINISTRATION AND COMPOSITIONS
Administration of the active compound and salts described herein can be via any of the accepted modes of administration for antiemesis agents.
The routes for administration include parenteral, oral, buccal, peroral, transdermal, intranosal or other suitable routes. Orally administrable compositions are preferred, since they are more convenient for general use.
Depending on the intended route of administration, such compositions may be formulated in conventional manner or other pharmaceutical systems for delivery of the drug in a rate and extent needed for the intended therapeutical use. The composition will include a conventional pharmaceutical carrier or excipient and an active compound of formula (I) or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
For solid compositions, conventional non toxic solid carriers including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like may be used. Liquid pharmaceutically
administerable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as defined above and optional pharmaceutical adjuvant in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or
suspension.
The following pharmacological data illustrate the invention.
Pharmacological data Inhibition of Apomorphine and Chemotherapy - induced Emesis
Male and female adult beagles (body weight 13-18 kg), bred at Morini Laboratories (CR, Italy), were individually housed and fed (300 g standard diet Altromin (Trade Mark)) two hours before the experiment with water ad libitum. 1) Inhibition of Apomorphine-induced Emesis
Dogs were given a subcutaneous injection of 0.1 mg/kg apomorphine, which reliably induces emesis within 5-10 minutes in all tested animals.
Protection against apomorphine-induced emesis is a measure of the test compound's dopamine antagonism at the chemoreceptor trigger zone in the area postrema. FCE 23884 was given subcutaneously (s.c.) 30 min before the agonist.
Number of emetic episodes and the latency of onset prior to the first expulsion of gastric content (latency time) were evaluated for each animal within two hours from
administration of the agonist.
2) Inhibition of Cisplatin-induced Emesis
FCE 23884 or the carrier or the reference compound (metoclopramide) were administered to dogs intravenously (i.v.) 30 min before and two hours after the intravenous injection of 3 mg/kg cisplatin. This dose of the
chemotherapic agent induced emesis in 100% of treated
animals .
The antiemetic effect was evaluated for five hours after the administration of the agonist.
The number of emetic episodes and the latency time for each dog were accounted for.
Results:
Inhibition of Apomorphine-induced Emesis
FCE 23884, at the dose of 50 μg/kg s.c, completely prevented the apomorphine - induced emesis in all treated animals; at the dose of 10 μg/kg s.c, 2/6 animals were still completely protected from emesis; with this dosage, the remaining dogs showed an increased latency time and a lower number of emetic responses. At the lowest dose (5μg/kg s.c.) the two treated animals vomited but they still showed a lower number of emetic episodes (see Table II).
2) Inhibition of Cisplatin-induced Emesis
FCE 23884, at the dose of 250 μg/kg i.v., completely antagonized cisplatin-induced emesis; at the dose of 125 μg/kg i.v., 3/4 dogs .were still completely protected from emesis; the remaining animal showed only one emetic response with a delayed latency time. At the lowest dose, (62.5 μg/kg i.v.), 1/4 animal was still quite protected (see Table II). The reference compound, metoclopramide, displayed the expected antagonistic effect at the dose of 6 mg/kg i.v.; indeed 5/6 treated animals were completely protected from emesis.
Conclusions
Subcutaneous and intravenous FCE 23884 exhibited definite activity against respectively apomorphine and chemotherapy induced emesis in the dog. The compound was extremely active in antagonizing apomorphine-induced emesis: 50 μg/kg s.c. completely protected from emesis all the treated animals; intravenously administered, FCE 23884, at
the dose of 125 μg/kg, almost completely inhibited the emetic responses following the administration of the cytotoxic agent.
Claims
CLAIMS 1. Use of a compound of the formula l
wherein n is 1 or 2, R1 represents a hydrogen atom or a C1-C4 alkyl group, R2 represents a hydrogen atom and R3 represents a hydrogen atom or a hydroxy group or R2 and R3 together represent a chemical bond, R4 represents a hydrogen atom or a phenyl or C1-C4 alkyl group, R5 represents a C1-C4 alkyl group or an allyl group and R6 represents a hydrogen or halogen atom; or a pharmaceutically acceptable salt thereof; in the preparation of a pharmaceutical composition for use in treating emesis.
2. Use according to claim 1, wherein the
pharmaceutical composition is for use in treatment of emesis induced by cancer therapy.
3. Use according to claim 1, wherein R1 is methyl.
4. Use according to claim 1, wherein R4 is methyl.
5. Use according to claim 1, wherein R5 is methyl.
6. Use according to claim 1, wherein the
substituent in the 8-position is in the β-configuration.
7. Use according to claim 1, wherein Rg is chlorine or bromine or hydrogen.
8. Use according to claim 1, in which the compound of formula I is 6-methyl-9, 10-didehydro-8β-(3,5-dioxopiperazin-1-yl-methyl)ergoline.
9. An agent for use in treating emesis, comprising a compound of formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof.
10. A method of treating emesis, which method comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula i as defined in claim 1 or a pharmaceutically acceptable salt thereof.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT89913149T ATE89729T1 (en) | 1988-10-21 | 1989-10-20 | EREGOLINE DERIVATIVES WITH ANTI-EMESIS EFFECT. |
DE1989606792 DE68906792T2 (en) | 1988-10-21 | 1989-10-20 | EREGOLIN SCREW-UP BODIES WITH ANTI-EMESIS EFFECT. |
KR1019900701311A KR900701273A (en) | 1988-10-21 | 1989-10-20 | Anti-Ecstatic Ergoline Derivatives |
DK149490A DK149490A (en) | 1988-10-21 | 1990-06-19 | ANTIEMETIC ERGOLINE DERIVATIVES |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB888824744A GB8824744D0 (en) | 1988-10-21 | 1988-10-21 | Antiemesis ergoline derivatives |
GB8824744.0 | 1988-10-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1990004396A1 true WO1990004396A1 (en) | 1990-05-03 |
Family
ID=10645610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1989/001263 WO1990004396A1 (en) | 1988-10-21 | 1989-10-20 | Antiemesis ergoline derivatives |
Country Status (12)
Country | Link |
---|---|
US (1) | US5202325A (en) |
EP (2) | EP0418327B1 (en) |
JP (1) | JPH03502802A (en) |
KR (1) | KR900701273A (en) |
AU (1) | AU626358B2 (en) |
CA (1) | CA2001004C (en) |
DK (1) | DK149490A (en) |
GB (1) | GB8824744D0 (en) |
HU (1) | HU208077B (en) |
IE (1) | IE63194B1 (en) |
IL (1) | IL91999A0 (en) |
WO (1) | WO1990004396A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0590971A1 (en) * | 1992-09-30 | 1994-04-06 | Eli Lilly And Company | 6-Heterocyclyl-4-amino-1,3,4,5-tetrahydrobenz CD indoles for treating motion sickness and vomiting |
EP0590970A1 (en) * | 1992-09-30 | 1994-04-06 | Eli Lilly And Company | 6-Heterocyclyl-4-amino-1,2,2a,3,4,5-hexahydrobenz CD indoles for treating motion sickness and vomiting |
US5627199A (en) * | 1991-03-28 | 1997-05-06 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz [CD] indoles |
US6303144B1 (en) | 1998-02-10 | 2001-10-16 | Welfide Corporation | Preparations with controlled release |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW252979B (en) * | 1992-12-24 | 1995-08-01 | Erba Carlo Spa |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2710246A1 (en) * | 1976-03-09 | 1977-09-22 | Richter Gedeon Vegyeszet | DELTA HOCH 8 -ERGOLEN- OR ERGOLINE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING SUCH AS AND METHOD FOR MANUFACTURING THE SAME |
EP0197241A1 (en) * | 1985-01-16 | 1986-10-15 | FARMITALIA CARLO ERBA S.r.l. | Piperazin-1-yl-ergoline derivatives, process for preparing them and pharmaceutical compositions containing them |
EP0218433A1 (en) * | 1985-10-01 | 1987-04-15 | Eli Lilly And Company | Selective method for blocking 5HT2 receptors |
EP0219257A2 (en) * | 1985-10-01 | 1987-04-22 | Eli Lilly And Company | Esters of dihydrolysergic acid |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3101535A1 (en) * | 1981-01-14 | 1982-08-12 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW (2-HALOGEN-ERGOLINYL) -N'.N'-DIETHYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
HU197569B (en) * | 1984-01-12 | 1989-04-28 | Sandoz Ag | Process for producing 8alpha-acylaminoergoline derivatives and pharmaceuticals comprising such compounds |
-
1988
- 1988-10-21 GB GB888824744A patent/GB8824744D0/en active Pending
-
1989
- 1989-10-16 IL IL91999A patent/IL91999A0/en not_active IP Right Cessation
- 1989-10-19 IE IE335889A patent/IE63194B1/en not_active IP Right Cessation
- 1989-10-19 CA CA002001004A patent/CA2001004C/en not_active Expired - Fee Related
- 1989-10-20 JP JP2500032A patent/JPH03502802A/en active Pending
- 1989-10-20 AU AU46336/89A patent/AU626358B2/en not_active Ceased
- 1989-10-20 WO PCT/EP1989/001263 patent/WO1990004396A1/en active IP Right Grant
- 1989-10-20 US US07/499,413 patent/US5202325A/en not_active Expired - Fee Related
- 1989-10-20 KR KR1019900701311A patent/KR900701273A/en not_active Application Discontinuation
- 1989-10-20 EP EP89913149A patent/EP0418327B1/en not_active Expired - Lifetime
- 1989-10-20 EP EP89119544A patent/EP0371246A1/en active Pending
- 1989-10-20 HU HU896835A patent/HU208077B/en not_active IP Right Cessation
-
1990
- 1990-06-19 DK DK149490A patent/DK149490A/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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DE2710246A1 (en) * | 1976-03-09 | 1977-09-22 | Richter Gedeon Vegyeszet | DELTA HOCH 8 -ERGOLEN- OR ERGOLINE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING SUCH AS AND METHOD FOR MANUFACTURING THE SAME |
EP0197241A1 (en) * | 1985-01-16 | 1986-10-15 | FARMITALIA CARLO ERBA S.r.l. | Piperazin-1-yl-ergoline derivatives, process for preparing them and pharmaceutical compositions containing them |
EP0218433A1 (en) * | 1985-10-01 | 1987-04-15 | Eli Lilly And Company | Selective method for blocking 5HT2 receptors |
EP0219257A2 (en) * | 1985-10-01 | 1987-04-22 | Eli Lilly And Company | Esters of dihydrolysergic acid |
Non-Patent Citations (2)
Title |
---|
Digestive Diseases and Sciences, Vol. 3, No. 5, May 1986, Plenum Publishing Corporation, R.S. ALPHIN et al.: "Antagonism of Cisplatin-Induced Emesis by Metoclopramide and Dazopride Through Enhancement of Gastric Motility", pages 524-529 * |
Martindale the Extra Pharmacopoeia, Twenty-Eighth Edition, 1982, The Pharmaceutical Press, (London, GB), pages 964-967 * |
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US5643930A (en) * | 1991-03-28 | 1997-07-01 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5,-tetrahydrobenz [cd]indoles |
US5750554A (en) * | 1991-03-28 | 1998-05-12 | Eli Lilly And Company | 6 heterocyclic-4-amino-1,3,4,5-tetrahydrobenz CD!indoles |
US5347013A (en) * | 1991-03-28 | 1994-09-13 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indoles |
US5364856A (en) * | 1991-03-28 | 1994-11-15 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[CD]indoles |
US5594019A (en) * | 1991-03-28 | 1997-01-14 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[CD]indoles |
US5624944A (en) * | 1991-03-28 | 1997-04-29 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[cd]indoles |
US5627199A (en) * | 1991-03-28 | 1997-05-06 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz [CD] indoles |
US5633273A (en) * | 1991-03-28 | 1997-05-27 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd] indoles |
US5641797A (en) * | 1991-03-28 | 1997-06-24 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[cd] indoles |
US5641794A (en) * | 1991-03-28 | 1997-06-24 | Eli Lilly Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indoles |
US5643934A (en) * | 1991-03-28 | 1997-07-01 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz [CD]indoles |
US5783590A (en) * | 1991-03-28 | 1998-07-21 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz CD!indoles |
US5654324A (en) * | 1991-03-28 | 1997-08-05 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz[cd]indoles |
US5648356A (en) * | 1991-03-28 | 1997-07-15 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[CD]indoles |
US5643910A (en) * | 1991-03-28 | 1997-07-01 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz[CD]indoles |
US5656653A (en) * | 1991-03-28 | 1997-08-12 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz[cd]indoles |
US5665744A (en) * | 1991-03-28 | 1997-09-09 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenzn [cd] indoles |
US5665743A (en) * | 1991-03-28 | 1997-09-09 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[CD] indoles |
US5665758A (en) * | 1991-03-28 | 1997-09-09 | Eli Lilly And Company | 6-Heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[CD] indoles |
US5674884A (en) * | 1991-03-28 | 1997-10-07 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz cd! indoles |
US5736562A (en) * | 1991-03-28 | 1998-04-07 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz CD ! indoles |
EP0590971A1 (en) * | 1992-09-30 | 1994-04-06 | Eli Lilly And Company | 6-Heterocyclyl-4-amino-1,3,4,5-tetrahydrobenz CD indoles for treating motion sickness and vomiting |
EP0590970A1 (en) * | 1992-09-30 | 1994-04-06 | Eli Lilly And Company | 6-Heterocyclyl-4-amino-1,2,2a,3,4,5-hexahydrobenz CD indoles for treating motion sickness and vomiting |
US6303144B1 (en) | 1998-02-10 | 2001-10-16 | Welfide Corporation | Preparations with controlled release |
Also Published As
Publication number | Publication date |
---|---|
KR900701273A (en) | 1990-12-01 |
DK149490D0 (en) | 1990-06-19 |
AU4633689A (en) | 1990-05-14 |
JPH03502802A (en) | 1991-06-27 |
GB8824744D0 (en) | 1988-11-30 |
HU208077B (en) | 1993-08-30 |
DK149490A (en) | 1990-08-16 |
HUT54049A (en) | 1991-01-28 |
CA2001004A1 (en) | 1990-04-21 |
EP0371246A1 (en) | 1990-06-06 |
IL91999A0 (en) | 1990-07-12 |
EP0418327A1 (en) | 1991-03-27 |
HU896835D0 (en) | 1990-11-28 |
US5202325A (en) | 1993-04-13 |
CA2001004C (en) | 1996-01-30 |
IE63194B1 (en) | 1995-04-05 |
IE893358L (en) | 1990-04-21 |
AU626358B2 (en) | 1992-07-30 |
EP0418327B1 (en) | 1993-05-26 |
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